Bone marrow transplantation (BMT) is increasingly used in humans for treatment of many life-threatening hematologic disorders, especially leukemia and certain immune deficiency diseases. However, graft-versus-host disease (GVHD) remains the major barrier for effective allogeneic bone marrow transplantation. This complication occurs in approximately 30% of bone marrow recipients. Up to half of those patients who develop GVHD may succumb to this process. This high morbidity and mortality has led to continuous interest in the possibility of controlling or preventing GVHD.
Current available approaches for prevention of GVHD include the use of non-specific immunosuppressive drugs, such as cyclosporine, methotrexate and/or prednisone. However, this treatment induces severe side effects, including nephrotoxicity, hypertension, hypercholesterolemia, diabetogenic effects, neurotoxicity, hirsutism and gengival hyperplasia. Moreover, the unselective depression of the entire immune system renders patients vulnerable to infections. In addition to the chronic administration of toxic, immunosuppressive agents, successful human allogeneic bone marrow transplantation depends, at the moment, on the availability of a suitable histocompatibility donor.
Clinicopathologically, two forms of GVHD have been recognized. Acute GVHD develops within the first 3 months after BMT and features disorders of skin, liver and gastrointestinal tract. Chronic GVHD is a multiorgan autoimmune-like disease, emerging from 3-month up to 3 years post-transplantation and shares features common to naturally occurring autoimmune disorders, like systemic lupus erythematosus (SLE) and scleroderma.
GVHD is caused by the competent donor T cells reacting against minor histocompatibility antigens of the recipient. The donor T cells are sensitized to such alloantigens and then directly, or through secondary signals, attack the host cells.
One approach for prevention of GVHD in murine models was recenty described by the inventors (Schlegel et al., 1994). The data reported therein show for the first time that GVHD can be prevented by administration of small peptides with high affinity for class II MHC molecules, and that the mechanism of prevention is MHC-associated. The precise mechanism of how these peptides prevent GVHD has still to be determined. However, the treatment with blocking peptides is limited by the specificity of the tested peptide to specific murine (or human) haplotype. Other disadvantages of using small peptides is the rapid clearance and the relatively short binding half-life to the MHC molecule.
The present invention relates to the use of a synthetic random copolymer consisting of glutamic acid (Glu), lysine (Lys), alanine (Ala) and tyrosine (Tyr) residues, in a relative molar ratio of 1.4-2.1 parts of Glu, 3.2-4.2 parts of Lys, and 4.0-6.0 parts of Ala to 1 part Tyr, with average molecular weight of 4,000-12,000, herein referred to as GLAT copolymer. The Glu, Lys, Ala and Tyr residues in the GLAT copolymer may all have the L (L-GLAT) or the D (D-GLAT) configuration, or some of the amino acid residues will have
A high molecular weight synthetic basic random copolymer consisting of L-Ala, L-Glu, L-Lys and L-Tyr residues in the molar ratio of about 6 parts Ala to 2 parts Glu to 4.5 parts Lys to 1 part Tyr, and having a molecular weight of 15,000-25,000, was first described in U.S. Pat. No. 3,849,550 as an agent for treatment or prevention of experimental allergic encephalomyelitis (EAE), a disease resembling multiple sclerosis (MS) that can be induced in susceptible animals. Batches of this copolymer of average molecular weight 23,000, designated Copolymer 1 or Cop 1, were shown to be highly effective in protecting and suppressing EAE in several animal species (Teitelbaum et al., 1971, 1974a, 1974b). Later, Cop 1 was found to significantly reduce the number of relapses in patients with the exacerbating-remitting form of MS (Bornstein et al., 1990; Sela et al., 1990; Johnson et al., 1994).
The mechanism underlying the therapeutic activity of Cop 1 in MS has been extensively studied. Cop 1 was found to be immunologically cross-reactive with myelin basic protein (MBP), the main autoantigen in EAE and MS. Its suppressive effect results from several mechanisms, such as inhibition of the autoreactive pathogenic T-cells on one hand (Teitelbaum et al., 1988), and stimulation of suppressor cells on the other hand (Aharoni et al., 1993). The first step essential for the activation of these specific processes is the binding of Cop 1 to the histo-compatibility molecules. Indeed, it has been shown that Cop 1-two different batches of molecular weight 5,550 and 8,600, and relative molar ratio of L-Ala (4.1-5.8 residues), L-Glu (1.4-1.8 residues), L-Lys (3.2-4.2 residues) and L-Tyr (1 residue)--binds very efficiently to a variety of MHC class II molecules of mouse and human origin, and furthermore competes with MBP and its major epitope p84-102 for MHC binding and can even displace such antigens that had already been bound to the MHC molecule (Fridkis-Hareli et al., 1994).
None of the prior art publications describes or suggests that Cop 1 may be used to prevent or to treat GVHD.